Aminoalcohol derivatives

ABSTRACT

A compound of the formula [Ig]; wherein R 1  is hydrogen or an amino protective group, R 2  is hydrogen or hydroxy, and R 3  and R 4  are independently N-methyl-methoxycarbonylamino, N-ethyl-methoxycarbonylamino, N-propyl-methoxycarbonylamino or 3-ethylureid, or R 3  and R 4  are both methoxycarbonylamino substituted at a meta position of the benzene rings, or a salt thereof, and (2S)-1-phenoxy-3-[3,3-bis[4-methoxycarbonylamino)-phenyl]propylamino]-2-propanol sulfate (2:1) and some crystal forms thereof as β 3 adrenergic receptor agonists.

TECHNICAL FIELD

[0001] This invention relates to new aminoalcohol derivatives and saltsthereof which are beta-3 (β₃) adrenergic receptor agonists and useful asa medicament.

DISCLOSURE OF INVENTION

[0002] This invention relates to new aminoalcohol derivatives which areβ₃ adrenergic receptor agonists, salts thereof and crystal formsthereof.

[0003] More particularly, it relates to new aminoalcohol derivatives,salts thereof and crystal forms thereof which have gut sympathomimetic,anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence,anti-pollakiuria activities, anti-diabetes and anti-obesity, toprocesses for the preparation thereof, to a pharmaceutical compositioncomprising the same and to a method of using the same therapeutically inthe treatment and/or prevention of gastro-intestinal disorders caused bysmooth muscle contractions in human beings or animal.

[0004] One object of this invention is to provide new and usefulaminoalcohol derivatives, salts thereof and crystal forms thereof whichhave gut sympathomimetic, anti-ulcerous, lipolytic, anti-urinaryincontinence, anti-pollakiuria activities, anti-diabetes andanti-obesity.

[0005] Another object of this invention is to provide processes for thepreparation of said aminoalcohol derivatives, salts thereof and crystalforms thereof.

[0006] A further object of this invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said aminoalcoholderivatives, salts thereof and crystal forms thereof.

[0007] Still further object of this invention is to provide atherapeutical method for the treatment and/or prevention of aforesaiddiseases in human beings or animals, using said aminoalcoholderivatives, salts thereof and crystal forms thereof.

[0008] The object compound of the present invention is the compound ofthe following formula [Is]:

[0009] namely,(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanolsulfate (2:1) [hereinafter referred to briefly as compound [Is]], or thecompound of the following formula [Ifm]:

[0010] namely,(2S)-1-phenoxy-3-[3,3-bis[3-(methoxycarbonylamino)-phenyl]propylamino]-2-propanol[hereinafter referred to briefly as compound [Ifm]], or a salt thereof.

[0011] The other object compound of the present invention can berepresented by the following general formula [Ig]:

[0012] wherein

[0013] R¹ is hydrogen or an amino protective group,

[0014] R² is hydrogen or hydroxy, and

[0015] R³ and R⁴ are independently N-methyl-methoxycarbonylamino,N-ethyl-methoxycarbonylamino, N-propyl-methoxycarbonylamino or3-ethylureid, or

[0016] R³ and R⁴ are both methoxycarbonylamino substituted at a metaposition of the benzene rings,

[0017] or a salt thereof.

[0018] We have already prepared(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolhydrochloride (1:1) [hereinafter referred to briefly as compound [Ih]],namely, a salt different from the compound [Is], and have filed aninternational patent application to cover the compound [Ih] as anapplication number of PCT/JP99/04538 (cf. Example 30) on Aug. 23, 1999,which was published as WO 00/12462. However, as we could not get thecompound [Ih] as crystals and pharmaceutical drugs are in generalstabler as crystals than as an amorphous powder, after filing theapplication, we prepared several different salts thereof and got thecompound [Is] as crystals. And, in such our research phase, we foundthat the compound [Is] exists as two polymorphic forms, i.e. Form Acrystallized from a solvent of ethanol as shown in Example 5 mentionedbelow and Form B crystallized from a solvent of acetone as shown inExample 6 mentioned below.

[0019] Further more, in our further research phase, we found that thecompound [Is] has a polymorphic form other than Forms A and Baforementioned, i.e. Form D crystallized from a mixed solvent ofethanol, methanol and acetone, or a mixed solvent of methanol andacetonitrile.

[0020] According to the present invention, the object compounds can beprepared by processes which are illustrated in the following schemes.

[0021] wherein R¹, R², R³ and R⁴ are each as defined above,

[0022] R_(a) ¹ is an amino protective group, and

[0023] R_(a) ⁵ is an amino protective group.

[0024] In the above and subsequent description of the presentspecification, suitable example of the various definition to be includedwithin the scope of the invention is explained in detail in thefollowing.

[0025] Suitable example of “amino protective group” moiety may be commonamino protective group such as acyl, for example, substituted orunsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl,trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g.tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted orunsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstitutedarenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl,ar(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in whichpreferable one is phenyl(lower)alkyl such as benzyl.

[0026] Suitable salts of the object aminoalcohol derivatives [Ifm] and[Ig] are pharmaceutically acceptable salts and include conventionalnon-toxic salts such as an inorganic acid addition salt [e.g.hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acidaddition salt [e.g. formate, acetate, trifluoroacetate, oxalate,maleate, fumarate, tartarate, citrate, methanesulfonate,benzenesulfonate, toluenesulfonate, etc.] or the like.

[0027] The Processes 1 to 5 for preparing the object compounds of thepresent invention are explained in detail in the following.

[0028] Process 1

[0029] The object compound [Ifa] or a salt thereof can be prepared byreacting a compound [II] with a compound [III] or a salt thereof.

[0030] Suitable salt of the compound [III] may be the same as thoseexemplified for the compound [Ig].

[0031] The reaction is preferably carried out in the presence of a basesuch as an alkali metal carbonate [e.g. sodium carbonate, potassiumcarbonate, etc.], an alkaline earth metal carbonate [e.g. magnesiumcarbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g.sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine[e.g. trimethylamine, triethylamine, etc.], picoline or the like.

[0032] The reaction is usually carried out in a conventional solvent,such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol,etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organicsolvent which does not adversely influence the reaction.

[0033] The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

[0034] Process 2

[0035] The object compound [If] or a salt thereof can be prepared bysubjecting a compound [Ifa] or a salt thereof to elimination reaction ofthe amino protective group.

[0036] Suitable salts of the compounds [If] and [Ifa] may be the same asthose exemplified for the compound [Ig].

[0037] This reaction is carried out in accordance with a conventionalmethod such as hydrolysis, reduction or the like.

[0038] The hydrolysis is preferably carried out in the presence of abase or an acid including Lewis acid.

[0039] Suitable base may include an inorganic base and an organic basesuch as an alkali metal [e.g. sodium, potassium, etc.], an alkalineearth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonateor bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo-[5.4.0]undec-7-ene, orthe like.

[0040] Suitable acid may include an organic acid [e.g. formic acid,acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid,etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride,etc.] and an acid addition salt compound [e.g. pyridine hydrochloride,etc.].

[0041] The elimination using trihaloacetic acid [e.g. trichloroaceticacid, trifluoroacetic acid, etc.] or the like is preferably carried outin the presence of cation trapping agents [e.g. anisole, phenol, etc.].

[0042] The reaction is usually carried out in a solvent such as water,an alcohol [e.g. methanol, ethanol, etc.], methylene chloride,chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof orany other solvent which does not adversely influence the reaction. Aliquid base or acid can also be used as the solvent. The reactiontemperature is not critical and the reaction is usually carried outunder cooling to heating.

[0043] The reduction method applicable for the elimination reaction mayinclude chemical reduction and catalytic reduction.

[0044] Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

[0045] Suitable catalysts to be used in catalytic reduction areconventional ones such as platinum catalysts [e.g. platinum plate,spongy platinum, platinum black, colloidal platinum, platinum oxide,platinum wire, etc.], palladium catalysts [e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raneynickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt,etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], coppercatalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] andthe like.

[0046] In case that the amino protective group is benzyl, the reductionis preferably carried out in the presence of a combination of palladiumcatalysts [e.g. palladium black, palladium on carbon, etc.] and formicacid or its salt [e.g. ammonium formate, etc.].

[0047] The reduction is usually carried out in a conventional solventwhich does not adversely influence the reaction such as water, analcohol [e.g. methanol, ethanol, propanol, etc.], chlorobenzene,N,N-dimethylformamide, or a mixture thereof. Additionally, in case thatthe above-mentioned acids to be used in chemical reduction are inliquid, they can also be used as a solvent. Further, a suitable solventto be used in catalytic reduction may be the above-mentioned solvent,and other conventional solvent such as diethyl ether, dioxane,tetrahydrofuran, etc. or a mixture thereof.

[0048] The reaction temperature of this reduction is not critical andthe reaction is usually carried out under cooling to heating.

[0049] Process 3

[0050] The object compound [Is] can be prepared by reacting the compound[Ifp] or a salt thereof other than sulfuric acid salt thereof withsulfuric acid.

[0051] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone,2-butanone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence the reaction, or the mixture thereof, preferablyethanol or acetone.

[0052] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0053] For example, the object compound [Is] can be prepared by themethod of Example 5 mentioned below.

[0054] Crystals of the object compound [Is] can be obtained

[0055] (1) in a process of crystallization of it which is carried out byconverting its free base (the compound [Ifp]) to it (semisulfate) in aconventional solvent using sulfuric acid as described in Process 3mentioned above (for example, the crystal Form A can be obtained asdescribed in Example 5 mentioned below),

[0056] (2) in a process of crystallization of it which is carried out bystating from a hot solution of it in a conventional solvent and coolingthe solution (for example, the crystal Form D, which has thecharacteristic diffraction angles 2θ (°) of about 6.41, about 9.70,about 16.85, about 17.93, about 20.82 and about 22.25 as shown in theFIG. 5 of the X-ray powder diffractometry pattern, can be obtained usinga mixed solvent of ethanol, methanol and acetone, or a mixed solvent ofmethanol and acetonitrile as a solvent of the hot solution),

[0057] (3) in a process of crystallization of it which is carried out bystarting from a solution of an oily, powder or amorphous compound [Is]in a conventional solvent and standing the solution under stirring (forexample, the crystal Form B can be obtained as described in Example 6mentioned below), or

[0058] (4) in a process of crystallization of it which is carried out bystarting from a solution of it in a conventional good solvent (e.g.methanol, etc.) and adding a conventional poor solvent (e.g. acetone,ethanol, isopropanol, etc.) to the solution.

[0059] Process 4

[0060] The object compound [Ig] or a salt thereof can be prepared byreacting a compound [II] with a compound [IV] or a salt thereof.

[0061] Suitable salt of the compound [IV] may be the same as thoseexemplified for the compound [Ig].

[0062] This reaction can be carried out in a similar manner to that ofthe aforementioned Process 1, and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of the Process 1.

[0063] Process 5

[0064] The object compound [Igb] or a salt thereof can be prepared bysubjecting a compound [Iga] or a salt thereof to elimination reaction ofthe amino protection group.

[0065] Suitable salts of the compounds [Iga] and [Igb] may be the sameas those exemplified for the compound [Ig].

[0066] This elimination reaction can be carried out in a similar mannerto that of the aforementioned Process 2, and therefore the reagents tobe used and the reaction conditions (e.g., solvent, reactiontemperature, etc.) can be referred to those of the Process 2.

[0067] The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like,and converted to the desired salt in conventional manners, if necessary.

[0068] It is to be noted that the compound [Ig] and the other compoundsmay include one or more stereoisomers due to asymmetric carbon atoms,and all of such isomers and mixture thereof are included within thescope of this invention.

[0069] It is further to be noted that isomerization or rearrangement ofthe object compound [Ig] may occur due to the effect of the light, acid,base or the like, and the compound obtained as the result of saidisomerization or rearrangement is also included within the scope of thepresent invention.

[0070] It is also to be noted that the solvating forms of the compounds[Is], [Ifm] and [Ig] (e.g. hydrate, acetone solvate, etc.) and any formsof the crystal of the compounds [Is], [Ifm] and [Ig] are included withinthe scope of the present invention.

[0071] The object compounds [Is], [Ifm] and [Ig] or a salt thereofpossess gut sympathomimetic, anti-ulcerous, anti-pancreatitis,lipolytic, anti-urinary incontinence and anti-pollakiuria activities,and are useful for the treatment and/or prevention of gastro-intestinaldisorders caused by smooth muscle contractions in human beings oranimals, and more particularly for the treatment and/or prevention ofspasm or hyperanakinesia in case of irritable bowel syndrome, gastritis,gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis,urinary calculus and the like; for the treatment and/or prevention ofulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causedby non steroidal anti-inflammatory drugs, or the like; for the treatmentand/or prevention of dysuria such as pollakiuria, urinary incontinenceor the like in case of nervous pollakiuria, neurogenic bladderdysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis,chronic prostatitis, prostatic hypertrophy or the like; for thetreatment and/or prevention of pancreatitis, obesity, diabetes,glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma,melancholia, depression or the like; for the treatment and/or preventionof diseases as the result of insulin resistance (e.g. hypertension,hyperinsulinemia, etc.); for the treatment and/or prevention ofneurogenetic inflammation; and for reducing a wasting condition, and thelike.

[0072] Additionally, β₃ adrenergic receptor agonists are known to lowertriglyceride and cholesterol levels and to raise high densitylipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly,the object compounds [Is], [Ifm] and [Ig] are useful in the treatmentand/or prevention of conditions such as hyper-triglyceridaemia,hypercholesterolaemia and in lowering high density lipoprotein levels aswell as in the treatment of atherosclerotic and cardiovascular diseasesand related conditions.

[0073] In order to show the usefulness of the compounds [Is], [Ifm] and[Ig] for the prophylactic and therapeutic treatment of above-mentioneddisease in human beings or animals, the pharmacological test data of arepresentative compound thereof are shown in the following.

[0074] Test

[0075] Effect on the increase in intravesical pressure induced bycarbachol in anesthetized dog

[0076] Test Compound

[0077] (1)(2S)-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanolsulfate (2:1) (crystal Form A)

[0078] Test Method

[0079] Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hoursand maintained under halothane anesthesia. A 12F Foley catheter waslubricated with water soluble jelly, inserted into the urethral orificeand advanced approximately 10 cm until the balloon tip was placed wellinside the bladder. The balloon was then inflated with 5 ml of room airand catheter slowly withdrawn just part the first resistance that isfelt at the bladder neck. Urine was completely drained out through thecatheter, and 30 ml of biological saline was infused. The catheter wasconnected to pressure transducer, and intravesical pressure wascontinuously recorded. The test compound was injected intravenously at 5minutes before the administration of carbachol (1.8 μg/kg). Test ResultsTreatment Increase in intravesical pressure (mmHg) Before 6.2 ± 1.1 Test Compound (1) 4.9 ± 0.9* (0.01 mg/kg)

[0080]2S-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanolsulfate (2:1) (compound [Is]) exists as two polymorphic forms, which aredesignated Form A (Example 5) and Form B (Example 6). These crystalforms can be characterized by X-ray powder diffractometry (XPD) anddifferential scanning calorimetry (DSC).

[0081] The 2θ values of X-ray diffraction peak for Form A are listed inthe following table. The characteristic diffraction angles of Form Awere about 6.51°, about 13.80°, about 16.97°, about 19.81°, about 21.95°and about 24.56°. Angle 2θ Relative Intensity (°) (%)  6.51 67 10.95 1112.97 34 13.80 35 14.91 17 16.15 11 16.97 39 17.83 36 19.27 58 19.81100  20.69 39 21.28 29 21.95 51 23.49 33 24.11 34 24.56 43 26.12 1527.07 15

[0082] The 2θ values of X-ray diffraction peak for Form B are listed inthe following table. The characteristic diffraction angles of Form Bwere about 6.29°, about 13.71°, about 18.20°, about 20.81° and about22.94°. Angle 2θ Relative Intensity (°) (%)  4.95 17  6.29 100   7.63 21 9.41 11 11.43  7 12.61 29 13.71 58 14.83 21 16.89 28 18.20 83 18.83 5819.95 64 20.81 70 22.94 39

[0083] X-ray powder diffraction was measured from 2.5° to 32.5° in 2θ,using Philips MPD1880 X-Ray Powder Diffraction System (Holland). Thesamples were illuminated with a graphite-monochromated Cu—Kα radiation(λ=1.5418 Å) at 40 mA and 30 kV. The goniometer was equipped with a 1°dispersion slit, a 0.2 mm receiving slit, and a 1° scatter slit. Aproportional counter was used for detection.

[0084] In the DSC measurement, Form A exhibited an endothermic peak dueto melting-decomposition at 224° C. (onset temperature). Form Bexhibited a small endothermic at 118° C. (onset temperature) due tomelting, followed by an exothermic peak due to thermal recrystallizationof Form C at 164° C. (peak top temperature) and an endothermic peak dueto melting-decomposition at 219° C. (onset temperature).

[0085] DSC6200 (Seiko Instruments, Japan) was used for these DSCmeasurements. Samples were weighed into aluminum pans (open system,aluminum plate covers were used) and empty pans were used as thereference. And measurements were carried out from room temperature toabout 270° C., with a heating rate of 10° C./min, under a nitrogenatmosphere (30 ml/min). A sampling time was 0.2 second.

[0086] Preferred embodiments of the object compound [Ig] are as follow:

[0087] R¹ is hydrogen,

[0088] R² is hydrogen, and

[0089] R³ and R⁴ are each N-methyl-methoxycarbonylamino.

[0090] The following Preparations and Examples are given for the purposeof illustrating this invention.

[0091] Preparation 1

[0092] To a mixture of 3,3-diphenylpropylamine (120 g), pyridine (53 ml)and dichloromethane (300 ml), trifluoroacetic anhydride (84 ml) wasadded dropwise below 10° C. After stirring for 30 minutes, the reactionmixture was added to a mixture of concentrated hydrochloric acid (20 ml)and ice-water (200 ml). The organic phase was separated, washed twicewith water, followed by washing with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered and evaporated toafford N-(3,3-diphenylpropyl)trifluoroacetamide (179 g).

[0093] Preparation 2

[0094] To a cooled mixture of 97% sulfuric acid (8 ml) and 70% nitricacid (7.8 ml), acetic anhydride (15.6 ml) was added dropwise below 20°C. To the reaction mixture, N-(3,3-diphenylpropyl)trifluoroacetamide(powdered, 7.80 g) was added. After stirring at room temperature for 1hour, the reaction mixture was added to ice-water, followed by additionof ethyl acetate (200 ml). The organic phase was washed successivelywith water (3 times) and saturated sodium chloride solution (once),dried over anhydrous magnesium sulfate, filtered and evaporated. Thecrude residue was purified by column chromatography (silica gel,toluene:ethyl acetate=20:1 to 4:1)) to affordN-[3,3-bis(4-nitrophenyl)propyl]trifluoroacetamide (6.46 g).

[0095] NMR (CDCl₃, δ): 2.45 (2H, quartet, J=7.3 Hz), 3.35 and 3.39 (2H,each t, J=7.8 Hz), 4.21 (1H, t, J=7.8 Hz), 6.41 (1H, br s), 7.42 (4H, d,J=8.7 Hz), 8.20 (4H, d, J=8.7 Hz)

[0096] Preparation 3

[0097] A mixture of N-[3,3-bis(4-nitrophenyl)propyl]-trifluoroacetamide(890 mg), iron powder (0.90 g), ammonium chloride (0.10 g), ethanol (9ml) and water (2 ml) was heated under reflux for 0.5 hour, cooled toroom temperature, filtered and evaporated. The residue was dissolved inethyl acetate, washed with water followed by saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andevaporated to afford N-[3,3-bis(4-aminophenyl)propyl]trifluoroacetamide(774 mg).

[0098] NMR (CDCl₃, δ): 2.22 (2H, quartet, J=7.3 Hz), 3.32 and 3.36 (2H,each t, J=6.6 Hz), 3.58 (4H, br s), 3.74 (1H, t, J=7.9 Hz), 6.12 (1H, brs), 6.61 (4H, d, J=8.4 Hz), 6.98 (4H, d, J=8.4 Hz)

[0099] MS m/z: 360 (M⁺+Na)

[0100] Preparation 4

[0101] To a mixture ofN-[3,3-bis(4-aminophenyl)propyl]-trifluoroacetamide (729 mg), pyridine(0.52 ml) and dichloromethane (5 ml), methyl chlorocarbonate (0.37 ml)was added below 10° C. After stirring at room temperature overnight, thereaction mixture was washed with water followed by saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andevaporated to affordN-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]-trifluoroacetamide(995 mg).

[0102] NMR (CDCl₃, δ): 2.29 (2H, quartet, J=7.8 Hz), 3.30 and 3.33 (2H,each t, J=6.5 Hz), 3.76 (6H, s), 3.87 (1H, t, J=7.9 Hz), 6.31 (1H, brs), 6.62 (2H, s), 7.13 (4H, d, J=8.6 Hz), 7.30 (4H, d, J=8.6 Hz)

[0103] MS m/z: 454 (M⁺+1)

[0104] Preparation 5

[0105] A mixture ofN-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propyl]trifluoroacetamide(500 mg), methanol (5 ml), 1,4-dioxane (5 ml), potassium carbonate (0.23g) and water (3 ml) was stirred at 40° C. After 2 hours, potassiumcarbonate (0.23 g) and water (5 ml) were added to the reaction mixtureand stirred at 50° C. for 3 hours. The reaction mixture was extractedwith ethyl acetate. The extracted ethyl acetate solution was dried overanhydrous potassium carbonate, filtered and evaporated to afford3,3-bis[4-(methoxycarbonylamino)phenyl]propylamine (458 mg) as a crudepowder.

[0106] NMR (CDCl₃, δ): 1.51 (2H, br s), 2.13 (2H, quartet, J=7.6 Hz),2.64 (2H, t, J=6.9 Hz), 3.75 (6H, s), 3.95 (1H, t, J=7.8 Hz), 6.56 (2H,s), 7.14 (4H, d, J=8.6 Hz), 7.28 (4H, d, J=7.1 Hz)

[0107] MS m/z: 358 (M⁺+1)

[0108] Preparation 6

[0109] A mixture of 3,3-bis[4-(methoxycarbonylamino)phenyl]-propylamine(69.3 g), benzaldehyde (24 ml) and 1,4-dioxane (200 ml) was heated underreflux for 1 hour. To the reaction mixture, sodium borohydride (8.8 g)was added portionally below 10° C., followed by dropwise addition ofmethanol (40 ml). After the reaction mixture was stirred at roomtemperature for 1 hour, water (0.5 l) and ethyl acetate (0.5 l) wereadded to the resulting mixture. The organic phase was separated, washedwith water (0.5 l×3 times) followed by saturated sodium chloridesolution (0.5 l), dried over anhydrous magnesium sulfate, filtered andevaporated. The crude residue was dissolved in ethyl acetate (200 ml)and therein was added 4N hydrogen chloride ethyl acetate solution (58ml) dropwise below 10° C. After standing for 20 minutes below 10° C.,hexane (200 ml) was added and the mixture was allowed to stand for 30minutes. The precipitated gummy product was separated by decantation,triturated with diisopropyl ether (300 ml) to afford a powder ofhydrochloride of the objective compound. After free basing the powder ina usual manner,N-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]amine (75.7 g)was obtained.

[0110] MS m/z: 448 (M⁺+1)

[0111] Preparation 7

[0112] To an ice-cooled solution ofN-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]amine (45.7 g)in methanol (120 ml), 4N hydrogen chloride in 1,4-dioxane (21 ml) wasadded dropwise. The mixture was evaporated to afford an oily residue.The residue was triturated with ethyl acetate (300 ml) to afford apowder, which was collected by filtration, washed with ethyl acetate anddried to affordN-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]-propyl]aminehydrochloride (39.7 g).

[0113] NMR (CDCl₃, δ): 2.34-2.47 (2H, m), 2.92-3.00 (2H, m), 3.71 (6H,s), 3.94 (1H, t, J=7.9 Hz), 4.15 (2H, s), 7.18 (4H, d, J=8.6 Hz), 7.36(4H, d, J=8.6 Hz)

[0114] Preparation 8

[0115] To a suspension ofN-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]aminehydrochloride (35.6 g) in methanol (100 ml) was added water (100 ml). Tothe mixture was added sodium hydrogen carbonate (8.4 g) portionwise.After 10 minutes stirring, the precipitate was dissolved. The mixturewas partitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were stirredwith saturated aqueous solution of sodium hydrogen carbonate at roomtemperature for 30 minutes. The organic layer was washed with brine,dried over magnesium sulfate and evaporated in vacuo to giveN-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]amine (34.4 g)as a brownish oil which was used for the next reaction without furtherpurification.

[0116] Preparation 9

[0117] To a suspension of powdered potassium carbonate (3.48 g) inN,N-dimethylformamide (39 ml) were added successivelyN-benzyl-3,3-bis[4-(methoxycarbonylamino)phenyl]propylaminehydrochloride (4.84 g) and benzyl bromide (1.44 ml) at room temperature.After the slight exothermic reaction was ceased, the mixture was stirredat room temperature for additional 1.5 hours and partitioned betweenhexane/ethyl acetate (1/1) and water. The organic layer was separated,washed successively with water and brine, dried over magnesium sulfate,and filtered. The filtrate was concentrated and the residue was purifiedby column chromatography (silica gel, hexane/ethyl acetate) to giveN,N-dibenzyl-3,3-bis[4-(methoxycarbonylamino)phenyl]-propylamine (5.30g) as a pale yellow amorphous powder.

[0118] NMR (CDCl₃, δ): 2.05-2.48 (4H, m), 3.52 (4H, s), 3.75 (6H, s),3.86 (1H, t, J=7 Hz), 6.52 (2H, br s), 7.00 (4H, d, J=8 Hz), 7.10-7.38(14H, m)

[0119] MS m/z: 538 (M⁺+1)

[0120] Preparation 10

[0121] To a suspension of lithium aluminum hydride (739 mg) intetrahydrofuran (21 ml) was added dropwiseN,N-dibenzyl-3,3-bis[4-(methoxycarbonylamino)phenyl]propylamine (5.24 g)in tetrahydrofuran (58 ml) at room temperature over 10 minutes, and themixture was heated at 60° C. for 5 hours. After allowed to cool to roomtemperature, the mixture was cooled with ice. Water (0.75 ml), 15%sodium hydroxide solution (0.75 ml), and water (2.2 ml) were addedsuccessively to the cooled mixture with vigorous stirring, and theprecipitate formed was removed by filtration. The filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, hexane/ethyl acetate) to giveN,N-dibenzyl-3,3-bis[4-(methylamino)phenyl]propylamine (2.43 g) as apale yellow oil.

[0122] NMR (CDCl₃, δ): 2.06-2.26 (2H, m), 2.34-2.50 (2H, m), 2.78 (6H,s), 3.53 (4H, s), 3.53 (2H, br s), 3.71 (1H, t, J=8 Hz), 6.47 (4H, d,J=8 Hz), 6.93 (4H, d, J=8 Hz), 7.12-7.42 (10H, m)

[0123] MS m/z: 450 (M⁺+1)

[0124] Preparation 11

[0125] To an ice-cooled solution of3,3-bis(3-aminophenyl)-N,N-dibenzyl-2-propen-1-amine (483 mg) indichloromethane (2.4 ml) were added pyridine (0.28 ml) and methylchlorocarbonate (0.21 ml). The mixture was stirred at the sametemperature for 1.5 hours and partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The organic layer was separated,washed with brine, dried over magnesium sulfate, and filtered. Thefiltrate was concentrated and the residue was purified by columnchromatography (silica gel, hexane/ethyl acetate) to giveN,N-dibenzyl-3,3-bis[3-(methoxycarbonylamino)phenyl]-2-propen-1-amine(561 mg) as a white amorphous powder.

[0126] NMR (CDCl₃, δ): 3.15 (2H, d, J=7 Hz), 3.57 (4H, s), 3.74 (3H, s),3.76 (3H, s), 6.22 (1H, t, J=7 Hz), 6.51 (2H, br s), 6.68-6.95 (4H, m),7.10-7.53 (14H, m) MS m/z: 536 (M⁺+1)

[0127] Preparation 12

[0128] The following compounds were obtained according to a similarmanner to that of Preparation 11.

[0129] (1)N,N-Dibenzyl-3,3-bis[4-[N-(methoxycarbonyl)-N-methylamino]phenyl]propylamine

[0130] NMR (CDCl₃, δ): 2.12-2.29 (2H, m), 2.32-2.50 (2H, m), 3.24 (6H,s), 3.54 (4H, s), 3.69 (6H, s), 3.93 (1H, t, J=7 Hz), 7.06 (8H, s),7.14-7.40 (10H, m)

[0131] MS m/z: 566 (M⁺+1)

[0132] (2)3-Dibenzylamino-1,1-bis[3-(methoxycarbonylamino)-phenyl]-1-propanol

[0133] NMR (CDCl₃, δ): 2.40-2.57 (2H, m), 2.57-2.75 (2H, m), 3.52 (4H,s), 3.75 (6H, s), 6.44 (2H, br s), 6.93 (2H, d, J=8 Hz), 7.04 (2H, s),7.12 (2H, t, J=8 Hz), 7.18-7.42 (12H, m), 7.75 (12H, br s)

[0134] MS m/z: 554 (M⁺+1)

[0135] Preparation 13

[0136] To a solution ofN,N-dibenzyl-3,3-bis[3-(methoxycarbonylamino)phenyl]-2-propen-1-amine(157 mg) in methanol (1.6 ml) was added 4N hydrogen chloride/1,4-dioxane(0.16 ml), and the mixture was hydrogenated (1 atm) over 20% palladiumhydroxide on carbon (17 mg) at room temperature for 4.5 hours. Thecatalyst was filtered off, the filtrate was evaporated, and the residuewas partitioned between ethyl acetate and saturated sodium bicarbonatesolution. The organic layer was separated, washed with brine, dried overmagnesium sulfate, and filtered. The filtrate was evaporated to giveN-benzyl-3,3-bis[3-(methoxycarbonyl-amino)phenyl]propylamine (146 mg) asa white amorphous powder.

[0137] NMR (CDCl₃, δ): 2.10-2.30 (2H, m), 2.50-2.68 (2H, m), 3.71 (2H,s), 3.74 (6H, s), 3.94 (1H, t, J=8 Hz), 6.79 (2H, br s), 6.85-6.98 (2H,m), 7.08-7.38 (11H, m)

[0138] MS m/z: 448 (M⁺+1)

[0139] Preparation 14

[0140] The following compounds were obtained according to a similarmanner to that of Preparation 13.

[0141] (1)N-Benzyl-3,3-bis[4-[N-(methoxycarbonyl)-N-methylamino]phenyl]propylamine

[0142] NMR (CDCl₃, δ): 2.12-2.33 (2H, m), 2.52-2.70 (2H, m), 3.26 (6H,s), 3.69 (6H, s), 3.73 (2H, s), 4.02 (1H, t, J=8 Hz), 7.02-7.40 (13H, m)

[0143] MS m/z: 476 (M⁺+1)

[0144] (2)3-Benzylamino-1,1-bis[3-(methoxycarbonylamino)phenyl]-1-propanol

[0145] NMR (CDCl₃, δ): 2.30-2.48 (2H, m), 2.73-2.89 (2H, m), 3.70 (2H,s), 3.75 (6H, s), 6.60 (2H, br s), 7.02-7.48 (13H, m)

[0146] MS m/z: 464 (M⁺+1)

[0147] (3) N-Benzyl-3,3-bis[4-(3-ethylureido)phenyl]propylamine

[0148] NMR (CDCl₃, δ): 1.14 (6H, t, J=7 Hz), 2.05-2.70 (4H, m), 3.25(4H, q, J=7 Hz), 3.71 (2H, s), 3.90-4.00 (1H, m), 4.60-4.80 (2H, m),7.00-7.20 (13H, m)

[0149] MS m/z: 474 (M⁺+1)

[0150] Preparation 15

[0151] To an ice-cooled solution ofN-benzyl-3,3-bis[4-(methoxycarbonylamino)phenyl]propylaminehydrochloride (4.84 g) in a mixture of 1,4-dioxane (14.5 ml) and 1Nsodium hydroxide solution (11.5 ml) was added dropwise di-tert-butyldicarbonate (2.32 g) in 1,4-dioxane (4.8 ml) over 5 minutes. The mixturewas stirred at room temperature for 1.5 hours before partitioned betweenethyl acetate and water. The organic layer was separated, washedsuccessively with water and brine, dried over magnesium sulfate, andfiltered. The filtrate was concentrated and the residue was purified bycolumn chromatography (silica gel, hexane/ethyl acetate) to giveN-benzyl-N-(tert-butoxycarbonyl)-3,3-bis[4(methoxycarbonylamino)phenyl]propylamine(5.66 g) as a pale yellow amorphous powder.

[0152] NMR (CDCl₃, δ): 1.44 (9H, s), 2.05-2.29 (2H, m), 2.94-3.22 (2H,m), 3.70 (1H, m), 3.75 (6H, s), 4.37 (2H, br s), 6.62 (2H, br s),6.98-7.37 (13H, m)

[0153] MS m/z: 570 (M++Na)

[0154] Preparation 16

[0155] To an ice-cooled suspension of sodium hydride (60% in mineraloil, 175 mg) in N,N-dimethylformamide (1 ml) was added dropwiseN-benzyl-N-(tert-butoxycarbonyl)-3,3-bis[4-(methoxycarbonylamino)phenyl]propylamine(1.09 g) in N,N-dimethylformamide (4.4 ml) over 5 minutes, and themixture was stirred at room temperature for 30 minutes before cooledwith ice. Iodoethane (0.40 ml) was added to the cooled mixture, and theresulting suspension was stirred at room temperature for 1.5 hours andpartitioned between hexane/ethyl acetate (1/1) and water. The organiclayer was separated, washed successively with water and brine, driedover magnesium sulfate, and filtered. The filtrate was concentrated togiveN-benzyl-N-(tert-butoxycarbonyl)-3,3-bis[4-[N-ethyl-N-(methoxycarbonyl)amino]phenyl]propylamine(1.29 g) as an oil.

[0156] NMR (CDCl₃, δ): 1.13 (6H, t, J=7 Hz), 1.44 (9H, s), 2.10-2.38(2H, m), 2.96-3.26 (2H, m), 3.67 (6H, s), 3.67 (4H, q, J=7 Hz),3.70-3.93 (1H, m), 4.22-4.48 (2H, m), 7.02-7.22 (8H, m), 7.22-7.36 (5H,m)

[0157] MS m/z: 626 (M⁺+Na)

[0158] Preparation 17

[0159] The following compound was obtained according to a similar mannerto that of Preparation 16.

[0160] N-Benzyl-N-(tert-butoxycarbonyl)-3,3-bis[4-[N-methoxycarbonyl)-N-propylamino]phenyl]propylamine

[0161] NMR (CDCl₃, δ): 0.87 (6H, t, J=7 Hz), 1.39-1.67 (4H, m), 1.44(9H, s), 2.10-2.38 (2H, m), 2.96-3.24 (2H, m), 3.48-3.66 (4H, m), 3.66(6H, s), 3.66-3.94 (1H, m), 4.22-4.49 (2H, br s), 6.98-7.39 (13H, m)

[0162] MS m/z: 654 (M⁺+Na)

[0163] Preparation 18

[0164] To an ice-cooled solution ofN-benzyl-N-(tert-butoxycarbonyl)-3,3-bis[4-[N-ethyl-N-(methoxycarbonyl)-amino]phenyl]propylamine(1.18 g) in dichloromethane (1.2 ml) was added 4N hydrogenchloride/1,4-dioxane (2.5 ml), and the mixture was stirred at roomtemperature for 1.5 hours. The mixture was concentrated, and the residuewas partitioned between ethyl acetate and saturated sodium bicarbonatesolution. The organic layer was separated, washed successively withwater and brine, dried over magnesium sulfate, and filtered. Thefiltrate was concentrated to giveN-benzyl-3,3-bis[4-[N-ethyl-N-(methoxycarbonyl)amino]phenyl]propylamine(1.13 g) as an oil.

[0165] NMR (CD₃OD, 6): 1.13 (6H, t, J=7 Hz), 2.14-2.36 (2H, m),2.52-2.70 (2H, m), 3.67 (6H, s), 3.67 (4H, q, J=7 Hz), 3.74 (2H, s),4.04 (1H, t, J=8 Hz), 6.98-7.40 (13H, m)

[0166] MS m/z: 504 (M⁺+1)

[0167] Preparation 19

[0168] The following compound was obtained according to a similar mannerto that of Preparation 18.

[0169]N-Benzyl-3,3-bis[4-[N-(methoxycarbonyl)-N-propylamino]phenyl]propylamine

[0170] NMR (CDCl₃, δ): 0.87 (6H, t, J=7 Hz), 1.39-1.67 (4H, m),2.12-2.36 (2H, m), 2.50-2.92 (2H, m), 3.46-3.68 (4H, m), 3.66 (6H, s),3.74 (2H, s), 4.03 (1H, t, J=8 Hz), 6.96-7.40 (13H, m)

[0171] MS m/z: 532 (M⁺+1)

[0172] Preparation 20

[0173] To a solution of 1,3-dibromobenzene (10.38 g) in tetrahydrofuran(88 ml) was added dropwise 1.54 M butyllithium/hexane (27 ml) at −70° C.over 45 minutes. The resulting suspension was allowed to warm to about−20° C. before cooled to −70° C. again. To the suspension was addeddropwise ethyl 3-(dibenzylamino)propionate (5.95 g) in tetrahydrofuran(12 ml) at about −65° C. over 10 minutes. The mixture was stirred at−70° C. for 1.5 hours and allowed to warm to room temperature for 1.5hours. The mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, washed successively with water and brine,dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, hexane/ethyl acetate) to give3-dibenzylamino-1,1-bis(3-bromophenyl)-1-propanol (9.38 g) as an oil.

[0174] NMR (CDCl₃, δ): 2.28-2.48 (2H, m), 2.58-2.76 (2H, m), 3.52 (4H,s), 6.90-7.52 (18H, m)

[0175] MS m/z: 564, 566, 568 (M⁺+1)

[0176] Preparation 21

[0177] A mixture of 3-dibenzylamino-1,1-bis(3-bromophenyl)-1-propanol(2.88 g) and p-toluenesulfonic acid monohydrate (2.89 g) in toluene (23ml) was heated to reflux for 2.5 hours. After allowed to cool to roomtemperature, the mixture was neutralized with saturated sodiumbicarbonate solution and extracted twice with ethyl acetate. Thecombined extract was washed successively with water and brine, driedover magnesium sulfate, and filtered. The filtrate was concentrated andthe residue was purified by column chromatography (silica gel,hexane/ethyl acetate) to giveN,N-dibenzyl-3,3-bis(3-bromophenyl)-2-propen-1-amine (2.38 g) as an oil.

[0178] NMR (CDCl₃, δ): 3.12 (2H, d, J=7 Hz), 3.57 (4H, s), 6.21 (1H, t,J=7 Hz), 6.90-7.48 (18H, m)

[0179] MS m/z: 546, 548, 550 (M⁺+1)

[0180] Preparation 22

[0181] A mixture of N,N-dibenzyl-3,3-bis(3-bromophenyl)-2-propen-1-amine(2.36 g), benzophenone imine (1.89 g),tris(dibenzylideneacetone)dipalladium(0) (200 mg), racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (318 mg), and sodiumtert-butoxide (906 mg) in toluene (11 ml) was heated at 80° C. for 1hour. The mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate, and filtered. The filtrate was concentrated and the residualred-brown oil was dissolved in tetrahydrofuran (12 ml). To the solutionwas added 6N hydrochloric acid (4.3 ml), and the mixture was stirred atroom temperature for 2.5 hours. The mixture was neutralized withsaturated sodium bicarbonate solution and extracted twice withchloroform. The combined extract was washed with brine, dried overmagnesium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by column chromatography (silica gel,chloroform/ethyl acetate) to give3,3-bis(3-aminophenyl)-N,N-dibenzyl-2-propen-1-amine (964 mg) as a paleyellow solid.

[0182] NMR (CDCl₃, δ): 3.15 (2H, d, J=7 Hz), 3.56 (4H, s), 3.56 (4H, brs), 6.17 (1H, t, J=7 Hz), 6.30-6.72 (6H, m), 6.93-7.48 (12H, m)

[0183] MS m/z: 420 (M⁺+1)

[0184] Preparation 23

[0185] The following compound was obtained according to a similar mannerto that of Preparation 22.

[0186] 1,1-Bis(3-aminopheyl)-3-dibenzylamino-1-propanol

[0187] NMR (CDCl₃, δ): 2.32-2.50 (2H, m), 2.56-2.78 (2H, m), 3.48 (4H,br s), 3.54 (4H, s), 6.44 (2H, dd, J=8 and 2 Hz), 6.59-6.75 (4H, m),6.96 (2H, t, J=8 Hz), 7.12-7.44 (10H, m)

[0188] MS m/z: 438 (M⁺+1)

[0189] Preparation 24

[0190] To a solution of1,1-bis(4-aminophenyl)-3-(dibenzylamino)-1-propanol (500 mg) intetrahydrofuran (5.0 ml) was added ethyl isocyanate (0.23 ml) dropwiseunder ice-water cooling. The mixture was stirred at the same temperaturefor 1 hour and at room temperature for 2 days. The reaction mixture wasevaporated in vacuo. The residue was purified by a silica gel columnchromatography (chloroform-ethyl acetate) to give1,1-bis[4-(3-ethylureido)phenyl]-3-dibenzylamino-1-propanol (566 mg) asa brownish amorphous powder.

[0191] NMR (CDCl₃, δ): 1.16 (6H, t, J=6 Hz), 2.36-2.70 (4H, m),3.14-3.36 (4H, m), 3.54 (4H, s), 4.70 (2H, s), 6.20 (2H, s), 6.96-7.36(18H, m)

[0192] Preparation 25

[0193] A mixture ofN-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]amine (33 g),(S)-2-(phenoxymethyl)oxirane (11.1 g) and 2-propanol (222 ml) was heatedat 90° C. for 13 hours and evaporated. The residue was purified by flushcolumn chromatography (silica gel, hexane:ethyl acetate=3:1 to 1:1) toafford(2S)-1-phenoxy-3-[N-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]-amino]-2-propanol(43.1 g).

[0194] NMR (CDCl₃, δ): 2.1-2.3 (2H, m), 2.4-2.7 (4H, m), 3.51 (1H, d,J=13.4 Hz), 3.75 (6H, s), 3.76 (1H, d, J=13.4 Hz), 3.8 (1H, m), 3.9 (1H,m), 3.93 (2H, s), 6.53 (12H, s), 6.86 (2H, d, J=8.0 Hz), 6.96 (1H, d,J=8.0 Hz), 7.06 (4H, m), 7.2-7.4 (11H, m)

[0195] MS m/z: 598 (M⁺+1)

[0196] Preparation 26

[0197] A mixture of (R)-2-(phenoxymethyl)oxirane (47 mg),N-benzyl-3,3-bis[4-(methoxycarbonylamino)phenyl]propylamine (140 mg) andethanol (2.0 ml) was heated under reflux for 18 hours. To the reactionmixture was added 10% palladium on carbon (50 mg). The mixture wasstirred at room temperature under hydrogen atmosphere for 6 hours. Themixture was filtered through Celite® and washed with ethanol. Thefiltrate and washings were combined and evaporated in vacuo. The residuewas purified by a silica gel column chromatography (chloroform/methanol)to give (2R)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanol (77 mg) as awhite amorphous powder.

[0198] NMR (CDCl₃, δ): 2.12-2.30 (2H, m), 2.50-2.82 (4H, m), 3.72 (6H,s), 3.84-4.10 (4H, m), 6.84-6.96 (3H, m), 7.14-7.38 (10H, m)

[0199] Preparation 27

[0200](2S)-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanol(50.7 mg) was dissolved in a solution of sulfuric acid (9.81 mg) inethanol (0.86 ml) and the resulting solution was evaporated in vacuo.The oily residue was powdered from a mixture of hexane and diisopropylether to afford(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (1:1) (45 mg) as a colorless powder.

[0201] NMR (CD₃OD, δ): 2.35-2.55 (2H, m), 2.95-3.05 (2H, m), 3.1-3.25(2H, m), 3.71 (6H, s), 3.91-4.1 (3H, m), 4.16-4.23 (1H, m), 6.90-6.98(3H, m), 7.18-7.31 (6H, m), 7.37 (4H, d, J=8.5 Hz)

[0202] Preparation 28

[0203](2S)-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanol(50.7 mg) and (S)-(+)-mandelic acid (15.2 mg) was dissolved in ethylacetate and the resulting solution was evaporated in vacuo. The oilyresidue was powdered from diisopropyl ether to afford(2S)-1-phenoxy-3-[3,3-bis[4-methoxycarbonylamino)phenyl]-propylamino]-2-propanol(S)-mandelate (1:1) (61 mg) as a powder.

[0204] NMR (CD₃OD, δ): 2.25-2.5 (2H, m), 2.9-3.0 (2H, m), 3.05-3.3 (2H,m), 3.71 (6H, s), 3.90-4.04 (3H, m), 4.07-4.20 (1H, m), 4.59 (1H, br s),6.86-6.98 (3H, m), 7.16-7.48 (15H, m)

[0205] Preparation 29

[0206](2S)-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanol(R)-mandelate (1:1) (60 mg, powder) was prepared from(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanol(50.7 mg) and (R)-(−)-mandelic acid (15.2 mg) in a similar manner tothat of Preparation 28.

[0207] NMR (CD₃OD, δ): 2.25-2.5 (2H, m), 2.9-3.0 (2H, m), 3.05-3.3 (2H,m), 3.71 (6H, s), 3.91-4.04 (3H, m), 4.07-4.19 (1H, m), 4.60 (1H, br s),6.90-6.98 (3H, m), 7.17-7.48 (15H, m)

[0208] Preparation 30

[0209] To a solution of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanol(504 mg) in ethanol (5 ml) was added citric acid (69 mg) at roomtemperature. The solution was evaporated in vacuo to give a colorlessoil. The residue was dissolved in hot ethanol (3.0 ml). Water (6.0 ml)was added to the ethanol solution in a boiling bath to give a slightlyclouded hot mixture. The mixture was stirred under ice-water cooling for3 hours. The precipitate was collected by vacuum filtration and washedwith cold ethanol-water (2:1) and then cold water to give a hygroscopicpowder. The wet mass was dried in vacuo at room temperature for 1 weekto give(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolcitrate (3:1) as a white powder (298 mg).

[0210] NMR (CD₃OD, δ): 2.16-2.50 (2H, m), 2.68 (2/3H, d, J=15 Hz), 2.78(2/3H, d, J=15 Hz), 2.86-3.24 (4H, m), 3.70 (6H, s), 3.86-4.30 (4H, m),6.86-7.00 (3H, m), 7.14-7.40 (10H, m)

[0211] Preparation 31

[0212] To a solution of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolin ethanol was added 1 equivalent of phosphoric acid (85% solution inwater) and the mixture was stirred at room temperature for 1 hour. Thesolvent was removed by evaporation and the residual viscous oil wasdissolved in ethyl acetate (1 volume/g). To the solution was addedhexane (2 volume/g) to give a crude salt as a paste. The paste wascollected by decantation of the solvent, triturated with hexane severaltimes, and dried under reduced pressure to give(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolphosphate (1:1) as a white powder.

[0213] NMR (CD₃OD, δ): 2.41-2.49 (2H, m), 2.91-3.26 (4H, m), 3.71 (6H,s), 3.91-3.99 (3H, m), 4.17-4.23 (1H, m), 6.88-6.97 (3H, m), 7.18-7.47(10H, m)

EXAMPLE 1

[0214] A mixture ofN-benzyl-3,3-bis[3-(methoxycarbonylamino)-phenyl]propylamine (118 mg)and (S)-2-(phenoxymethyl)oxirane (56 mg) in ethanol (1.2 ml) was heatedunder reflux for 2 hours. After allowed to cool to room temperature, themixture was concentrated and the residue was purified by columnchromatography (silica gel, hexane/ethyl acetate) to give(2S)-1-phenoxy-3-[N-benzyl-3,3-bis[3-(methoxycarbonylamino)phenyl]propylamino]-2-propanol(119 mg) as a white amorphous powder.

[0215] NMR (CDCl₃, δ): 2.06-2.36 (2H, m), 2.36-2.73 (4H, m), 3.52 (1H,d, J-13 Hz), 3.75 (6H, s), 3.76 (1H, d, J=13 Hz), 3.78-4.02 (4H, m),6.57 (2H, s), 6.73-7.38 (18H, m)

[0216] MS m/z: 598 (M⁺+1)

EXAMPLE 2

[0217] The following compounds were obtained according to a similarmanner to that of Example 1.

[0218] (1)(2S)-1-Phenoxy-3-[N-benzyl-3,3-bis[4-[N-(methoxycarbonyl)-N-methylamino]phenyl]propylamino]-2-propanol

[0219] NMR (CDCl₃, δ): 2.10-2.72 (6H, m), 3.25 (6H, s), 3.53 (1H, d,J=13 Hz), 3.69 (6H, s), 3.76 (1H, d, J=13 Hz), 3.82-4.00 (4H, m),6.78-7.38 (18H, m)

[0220] MS m/z: 626 (M⁺+1)

[0221] (2)(2S)-1-Phenoxy-3-[N-benzyl-3,3-bis[4-[N-ethyl-N-(methoxycarbonyl)amino]phenyl]propylamino]-2-propanol

[0222] NMR (CDCl₃, δ): 1.12 (6H, t, J=7 Hz), 2.09-2.38 (2H, m),2.38-2.75 (4H, m), 3.53 (1H, d, J=13 Hz), 3.66 (6H, s), 3.66 (4H, q, J=7Hz), 3.76 (1H, d, J=13 Hz), 3.79-4.00 (4H, m), 6.80-7.38 (18H, m)

[0223] MS m/z: 676 (M⁺+Na)

[0224] (3)(2S)-1-Phenoxy-3-[N-benzyl-3,3-bis[4-[N-(methoxycarbonyl)-N-propylamino]phenyl]propylamino]-2-propanol

[0225] NMR (CDCl₃, δ): 0.87 (6H, t, J=7 Hz), 1.40-1.66 (4H, m),2.08-2.78 (6H, m), 3.42-4.02 (10H, m), 3.66 (6H, s), 6.79-7.40 (18H, m)

[0226] MS m/z: 682 (M⁺+1)

[0227] (4)(2S)-1-Phenoxy-3-[N-benzyl-3-hydroxy-3,3-bis[3-(methoxycarbonylamino)phenyl]propylamino]-2-propanol

[0228] NMR (CDCl₃, δ): 2.40-2.63 (4H, m), 2.67-2.86 (2H, m), 3.48-3.90(5H, m), 3.76 (6H, s), 6.57 (2H, br s), 6.68-7.40 (18H, m), 7.52 (1H, brs)

[0229] MS m/z: 614 (M⁺+1)

[0230] (5)(2S)-1-Phenoxy-3-[N-benzyl-3,3-bis[4-(3-ethylureido)-phenyl]propylamino]-2-propanol

[0231] NMR (CDCl₃, δ): 1.08 (6H, t, J=7 Hz), 1.98-2.66 (6H, m),3.10-3.33 (4H, m), 3.47 (1H, d, J=13 Hz), 3.68-3.98 (4H, m), 3.72 (1H,d, J=13 Hz), 5.29 (2H, br s), 6.73-7.34 (18H, m)

[0232] MS m/z: 624 (M⁺+1)

EXAMPLE 3

[0233] A solution of(2S)-1-phenoxy-3-[N-benzyl-3,3-bis[3-(methoxycarbonylamino)phenyl]propylamino]-2-propanol(105 mg) in methanol (2.1 ml) was hydrogenated (1 atm) over 10%palladium on carbon (15 mg) at room temperature for 24 hours.

[0234] After the catalyst was filtered off, the filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, chloroform/methanol) to give(2S)-1-phenoxy-3-[3,3-bis[3-(methoxycarbonylamino)phenyl]-propylamino]-2-propanol(77 mg) as a white amorphous powder.

[0235] IR (Neat): 1710, 1600, 1548, 1492, 1446, 1242 cm⁻¹

[0236] NMR (CDCl₃, δ): 2.06-2.40 (2H, m), 2.47-2.94 (4H, m), 3.76(6H,s), 3.78-4.21 (4H, m), 6.66-7.48 (15H, m)

[0237] MS m/z: 508 (M⁺+1)

EXAMPLE 4

[0238] The following compounds were obtained according to a similarmanner to that of Example 3.

[0239] (1)(2S)-1-Phenoxy-3-[3,3-bis[4-[N-(methoxycarbonyl)-N-methylamino]phenyl]propylamino]-2-propanol

[0240] NMR (CDCl₃, δ): 2.12-2.42 (4H, m), 2.55-2.89 (3H, m), 3.26 (6H,s), 3.69 (6H, s), 3.85-4.12 (3H, m), 6.83-7.02 (2H, m), 7.06-7.36 (11H,m)

[0241] MS m/z: 536 (M⁺+1)

[0242] (2)(2S)-1-Phenoxy-3-[3,3-bis[4-[N-ethyl-N-(methoxycarbonyl)amino]phenyl]propylamino]-2-propanol

[0243] NMR (CDCl₃, δ): 1.13 (6H, t, J=7 Hz), 2.16-2.37 (2H, m),2.57-2.93 (4H, m), 3.67 (6H, s), 3.67 (4H, q, J=7 Hz), 3.87-4.12 (4H,m), 6.81-7.39 (13H, m)

[0244] MS m/z: 564 (M⁺+1)

[0245] (3)(2S)-1-Phenoxy-3-[3,3-bis[4-[N-(methoxycarbonyl)-N-propylamino]phenyl]propylamino]-2-propanol

[0246] NMR (CDCl₃, δ): 0.87 (6H, t, J=7 Hz), 1.41-1.67 (4H, m),2.15-2.37 (2H, m), 2.56-2.92 (4H, m), 3.48-3.66 (4H, m), 3.67 (6H, s),3.88-4.10 (4H, m), 6.81-7.38 (13H, m)

[0247] MS m/z: 592 (M⁺+1)

[0248] (4)(2S)-1-Phenoxy-3-[3-hydroxy-3,3-bis[3-(methoxycarbonylamino)phenyl]propylamino]-2-propanol

[0249] IR (KBr): 1710, 1602, 1548, 1492, 1442, 1238 cm⁻¹

[0250] NMR (CDCl₃, δ): 2.24-2.60 (2H, m), 2.60-2.95 (4H, m), 3.70 (6H,s), 3.75-4.18 (3H, m), 6.76-7.50 (15H, m)

[0251] MS m/z: 524 (M⁺+1)

[0252] (5)(2S)-1-Phenoxy-3-[3,3-bis[4-(3-ethylureido)phenyl]-propylamino]-2-propanol

[0253] IR (KBr): 1658 cm⁻¹

[0254] NMR (CD₃OD, δ): 1.13 (6H, t, J=7 Hz), 2.10-2.50 (2H, m),2.71-3.11 (4H, m), 3.20 (4H, q, J=7 Hz), 3.80-4.22 (4H, m), 6.82-7.40(13H, m)

[0255] MS m/z: 534 (M⁺+1)

EXAMPLE 5

[0256] Preparation of crystal Form A of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1)

[0257] A mixture of(2S)-1-phenoxy-3-[N-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl]propyl]amino]-2-propanol(94.71 g), methanol (1 l) and wet 10% palladium on charcoal (10 g) wasstirred under hydrogen (1 atm) at room temperature for 2 hours, filteredand evaporated to afford(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolas a crude product. To an ethanol (200 ml) solution of the crudeproduct, an ethanol (64 ml) solution of 96% sulfuric acid (8.1 g) wasadded dropwise below 10° C. The reaction mixture was stirred at roomtemperature overnight to precipitate colorless crystals, which werecollected by filtration (The filtrated solution was used in Example 6.),washed with ethanol and dried to afford crystal Form A of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonyl-amino)phenyl]propylamino]-2-propanolsulfate (2:1) (54.9 g).

[0258] NMR (CD₃OD, δ): 2.4-2.6 (2H, m), 2.9-3.0 (2H, m), 3.0-3.2 (2H,m), 3.70 (6H, s), 3.9-4.0 (3H, m), 4.2-4.4 (1H, m), 6.88-6.95 (3H, m),7.16-7.37 (10H, m)

EXAMPLE 6

[0259] Preparation of crystal Form B of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1)

[0260] The filtrated solution in Example 5 was evaporated to afford anoily residue which was dissolved in acetone (80 ml). The resultingsolution was stirred at room temperature for 1.5 hours to precipitatecolorless crystals, which were collected by filtration, washed withacetone and dried to afford crystal Form B of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1) (3.0 g).

[0261] Acetone solvate of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1) was obtained in a process of preparation of the crystalForm B.

DESCRIPTION OF THE FIGURES

[0262]FIG. 1 is an XPD pattern for crystal Form A of compound [Is]

[0263]FIG. 2 is an XPD pattern for crystal Form B of compound [Is]

[0264]FIG. 3 is a DSC curve for crystal Form A of compound [Is]

[0265]FIG. 4 is a DSC curve for crystal Form B of compound [Is]

[0266]FIG. 5 is an XPD pattern for crystal Form D of compound [Is]

1. A compound of the formula [Is]:

(2S)-1-Phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)-phenyl]propylamino]-2-propanolsulfate (2:1).
 2. Crystalline(2S)-1-phenoxy-3-[3,3-bis[4-(methoxy-carbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1).
 3. A crystal Form A of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1) which shows the peaks at the diffraction angles shown inthe following in its X-ray powder diffractometry pattern: characteristicdiffraction angle 2θ (°): about 6.51, about 13.80, about 16.97, about19.81, about 21.95 and about 24.56.
 4. A crystal Form B of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1) which shows the peaks at the diffraction angles shown inthe following in its X-ray powder diffractometry pattern: characteristicdiffraction angle 2θ (°): about 6.29, about 13.71, about 18.20, about20.81 and about 22.94.
 5. A crystal Form D of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolsulfate (2:1) which shows the peaks at the diffraction angles shown inthe following in its X-ray powder diffractometry pattern: characteristicdiffraction angle 2θ (°): about 6.41, about 9.70, about 16.85, about17.93, about 20.82 and about 22.25.
 6. A process for preparing thecompound of claim 1, which comprises reacting a compound of(2S)-1-phenoxy-3-[3,3-bis[4-(methoxycarbonylamino)phenyl]propylamino]-2-propanolor a salt thereof other than sulfate thereof with sulfuric acid.
 7. Acompound of the formula [Ig]:

wherein R¹ is hydrogen or an amino protective group, R² is hydrogen orhydroxy, and R³ and R⁴ are independently N-methyl-methoxycarbonylamino,N-ethyl-methoxycarbonylamino, N-propyl-methoxycarbonylamino or3-ethylureido, or R³ and R⁴ are both methoxycarbonylamino substituted ata meta position of the benzene rings, or a salt thereof.
 8. Apharmaceutical composition which comprises, as an active ingredient, acompound of claim 1 to 5 and 7 or a pharmaceutically acceptable saltthereof in admixture with pharmaceutically acceptable carriers orexcipients.
 9. Use of a compound of claim 1 to 5 and 7 or apharmaceutically acceptable salt thereof for the manufacture of amedicament.
 10. A compound of claim 1 to 5 and 7 or a pharmaceuticallyacceptable salt thereof for use as a medicament.
 11. A method for theprophylactic and/or therapeutic treatment of pollakiuria, urinaryincontinence, obesity or diabetes, which comprises administering acompound of claim 1 to 5 and 7 or a pharmaceutically acceptable saltthereof to a human being or an animal.